1. Field of the Invention
The present invention relates to a method of evaluating fatty liver related disease, a fatty liver related disease-evaluating apparatus, a fatty liver related disease-evaluating method, a fatty liver related disease-evaluating program product, a fatty liver related disease-evaluating system, and information communication terminal apparatus, which utilize a concentration of an amino acid in blood (including, for example, plasma, serum, and the like) and a method of searching for prophylactic/ameliorating substance for fatty liver related disease which searches a substance for preventing a fatty liver related disease or ameliorating a state of a fatty liver related disease.
2. Description of the Related Art
Non-alcoholic steatohepatitis (NASH) and non-alcoholic fatty liver disease (NAFLD) are liver symptoms that are generally based on fatty liver (accumulation of fat droplets in hepatic cells) diagnosed by ultrasonic diagnosis and present a hepatic histological image similar to that of an alcoholic liver disorder in terms of a hepatic histological finding although the patient has no history of excessive alcohol drinking and is not infected with hepatitis virus (“Guide for Diagnosis of NASH/NAFLD, 2010, edited by Japan Society of Hepatology”). The liver disorder characterized principally by large droplet liver fat deposition is called NAFLD, and NAFLD is further classified into simple steatosis that has good prognosis, and NASH that is progressive and ultimately leads to hepatic cirrhosis (“Guide for Diagnosis of NASH/NAFLD, 2010, edited by Japan Society of Hepatology”).
Historically, Ludwig reported in 1980, as NASH, a case where although having no history of excessive drinking, a patient had an alcoholic liver disorder leading to hepatic cirrhosis, and in 1986, Schaffner reported a group of diseases of NAFLD. Regarding the hepatic histological image of NAFLD, mention is made of Matteoni's four-type classification (type 1: simple steatosis; type 2: fatty hepatitis; type 3: fatty hepatic necrosis with balloon-like degeneration; and type 4: hepatic cell necrosis with Mallory body or fibrogenesis), and type 3 and type 4, with which the frequency of development to hepatic cirrhosis or liver-related death is high, belong to NASH. Regarding NASH, mention is made of Brunt's four-type classification by the degree of fibrogenesis (Stage 1: lobulus center; Stage 2: from lobulus center to portal vein area; Stage 3: bridging; and Stage 4: hepatic cirrhosis).
NASH and NAFLD strongly correlate with obesity or metabolic syndrome. In the obesity group, type 1 of NAFLD constitutes 60% to 70%, type 3 or type 4 of NAFLD (i.e. NASH) constitutes 20% to 25%, and hepatic cirrhosis (i.e. Stage 4 of NASH) constitutes 2% to 3%. Further, the frequencies of combination with lipid metabolism abnormality, high blood pressure, and hyperglycemia in NASH are 60%, 60%, and 30%, respectively, and the frequency of combination with metabolic syndrome is as high as about 50%.
Fatty liver, on which NASH and NAFLD are based, is found in 20% to 30% of all medical examination examinees, and has tended to increase in recent years as in the case of metabolic syndrome. In association with development of the hepatic symptom from fatty liver to NAFLD and to NASH, NAFLD is found in 8% of medical examination examinees, and the frequency of NASH is estimated to be 0.5% to 1% of adults. Prognosis of NASH is poor, and in NASH, development to fibrogenesis has been found in 25% of the patients and development to hepatic cirrhosis has been found in 15% of the patients over five years, and the survival rate of HASH is 67% for five years, and 59% for ten years.
Regarding the mechanism of onset of NAFLD and NASH, the “two-hit theory” is accepted in which first, fat accumulation occurs in hepatic cells, and then a factor of hepatic cell disorder such as oxidation stress is added, leading to onset of the disease. Regarding the treatment of NAFLD and NASH, exercise and dietary therapies for amelioration of obesity, and drug therapies using insulin resistance improving agents, biguanide agents, ursodeoxycholic acid, antihyperlipemic agents, antioxidants, and the like are examined, but therapies using control are scarcely examined.
For definite diagnosis of NAFLD and NASH, hepatic histological images from liver biopsy are required. However, liver biopsy is highly invasive, and gives pain to patients, and further has a risk of bleeding or the like, etc. so that patients are placed under a great burden. Therefore, it is almost practically impossible to subject 20% to 30% of all medical examination examinees, i.e. those that are found to have fatty liver, to liver biopsy.
In view of these situations, it is desired from the viewpoint of a physical burden of patients and medical economy that cases with a high possibility of NASH or NAFLD be first discriminated using a less-invasive simple and convenient method in lieu of liver biopsy, and the discriminated cases be determined as objects to be subjected to NASH diagnosis by liver biopsy and objects to be treated.
As low-invasive methods for discriminating NAFLD and NASH, transaminase (ALT>AST), a rise in γ GTP, an increase in AST/ALT ratio, a fibrogenesis marker such as hyaluronic acid, a decrease in blood platelet count, a HOMA index representing insulin resistance, an oxidation stress marker, an adipocyte-pokine such as adiponectin, a high-sensitivity CRP and so on have been heretofore reported (“Guide for Diagnosis of NASH/NAFLD, 2010, edited by Japan Society of Hepatology” and “Aliment Pharmacol Ther, 2011, 33, 525-540”).
An index using a blood amino acid concentration for diagnosis of a liver disease is a Fischer ratio “(Leu+Val+Ile)/(Phe+Tyr)” proposed by Fischer, or a BTR index “(Leu+Val+Ile)/Tyr”, a simplified form of the Fischer ratio, which is used for the same purpose as that of the Fischer ratio (“Fischer J E, Surgery, 1975, 78, 276-290”).
WO 2004/052191, WO 2006/098192 and WO 2009/054351 related to a method of relating the amino acid concentration and a biological state are disclosed as previous patents. In WO 2004/052191, a method of diagnosing a hepatitis using a blood amino acid and an index for the purposes of discriminating between hepatitis-free and hepatitis in hepatitis C are disclosed. WO 2006/129513 related to an apparatus that evaluates a progress of a disease state of hepatic disease using index formula composed of a fractional expression having a concentration of an amino acid as an explanatory variable, is disclosed. WO 2008/015929 related to a method of evaluating a state of metabolic syndrome using amino acid concentration, WO 2009/001862 related to a method of evaluating a state of visceral fat accumulation using amino acid concentration, WO 2009/054350 related to a method of evaluating a state of impaired glucose tolerance using amino acid concentration, and WO 2010/095682 related to a method of evaluating states of apparent obesity, non-apparent obesity and obesity using amino acid concentration, are disclosed.
However, neither correlation of fatty liver, NAFLD, and NASH with a blood amino acid concentration nor application of a blood amino acid concentration to a method for discriminating fatty liver, NAFLD, and NASH has been heretofore reported. The discrimination methods reported in the documents “Guide for Diagnosis of NASH/NAFLD, 2010, edited by Japan Society of Hepatology” and “Aliment Pharmacol Ther, 2011, 33, 525-540” do not have sufficient diagnosis performance, and it is therefore difficult to apply the discrimination method as established diagnosis methods. The Fischer ratio and BTR index reported in the document “Fischer J E, Surgery, 1975, 78, 276-290” are used for diagnosis of hepatic encephalopathy, and therefore sufficient accuracy cannot be achieved when the Fischer ratio and BTR index are used for diagnosis of NAFLD or NASH. When the index formulae disclosed in WO 2004/052191, WO 2006/098192, WO 2009/054351, WO 2006/129513, WO 2008/015929, WO 2009/001862, WO 2009/054350 and WO 2010/095682 are used for diagnosis of NAFLD or NASH, sufficient accuracy cannot be achieved because diagnosis objects are different.
That is, there is the problem that a method for evaluating a state of fatty liver related diseases such as fatty liver, NAFLD, and NASH with a plurality of amino acids as explanatory variables has not been heretofore developed and put to practical use.